Systemic allergic reaction to galcanezumab (emgality): a case report

Abstract

Background

A previously unreported systemic reaction to Galcanezumab (Emgality) is described. Galcanezumab is a humanized monoclonal antibody designed to bind to calcitonin gene-related peptide, a neuropeptide associated with neurogenic inflammation during migraine attacks. Although clinical trials showed that Galcanezumab had few adverse reactions (injection site related erythema, pruritus, and swelling), no systemic drug reactions have been noted.

Case report

A 50-year-old female with chronic migraine, mast cell disorder, Hashimoto’s disease, positive antinuclear antibody and positive anti-cyclic citrullinated peptide antibody not on immune modulators received the initial dose of galcanezumab 240 mg after failing multiple migraine treatments. The following day, she developed injection site reaction, malar erythema and flu-like symptoms. Symptoms progressed the second day after injection, and she developed swelling in her lips and throat. Intravenous steroid and antihistamines improved airway symptoms, and the remaining symptoms improved after a course of oral steroids.

Conclusions

Delayed system allergic reaction to Galcanezumab requiring emergency intervention may occur. A history of autoimmune disorder may be a predisposing factor.

Introduction

Recent studies have shown the prominent role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology (1,2). CGRP is expressed throughout the trigeminovascular system and central nervous system, and it is implicated in sensory neuromodulation, vasodilation and mediation of neurogenic inflammation (1). Elevated blood levels of CGRP have been found during migraine attacks (1). Galcanezumab (Emgality) is a humanized monoclonal antibody (mAb) designed to bind to CGRP and prevent its biological activity without blocking the CGRP receptor (1).

The Efficacy and Safety of Galcanezumab for the Prevention of Episodic Migraine (EVOLVE-2) trial showed that Galcanezumab treatment groups experienced a 4.3-day reduction in monthly migraine headache days compared to the placebo group (1). In addition, few adverse reactions were noted in in the treatment group compared to the placebo group: injection site reaction (7.9%), injection site erythema (3.1%), injection site pruritus (3.1%) and injection site swelling (2.2%) (1). These findings were corroborated by a meta-analysis in 2019, which demonstrated that CGRP mAb reduced migraine frequency by at least 50% compared to placebo (3). The study also determined that injection discomfort was the only statistically significant adverse event between the groups (3). When galcanezumab was released to market, no systemic reactions had been noted. Subsequent reports note that mAb can trigger immunoallergic reactions, a possible increased risk of developing or worsening hypertension and constipation. This case report describes a previously unreported systemic allergic reaction in a patient who received galcanezumab.

Case report

A 50-year-old female with chronic migraine, an unspecified mast cell activation syndrome (MCAS), Hashimoto’s disease, mildly intermittently positive antinuclear antibody and positive anti-cyclic citrullinated peptide antibody without rheumatoid arthritis symptoms presented with persistent migraines. She was not on any immune modulating treatment for these markers and took cetirizine 10 mg, ranitidine 150 mg twice daily and diphenhydramine as needed for the mast cell disorder.

She described the migraines as a severe sharp pressure located in her occipital region. The migraines were associated with photophobia, phonophobia, nausea and vomiting. Her symptoms interfered with her activities. She had tried carbamazepine, amitriptyline, venlafaxine, duloxetine and propranolol without relief. Botulinum toxin injection reduced headache frequency from more than 20 days/month to 8–10 days/month, but headaches still limited activity on those days.

Because of the persistence of migraine, galcanezumab was started. She received two subcutaneous injections of Galcanezumab 120 mg to her left deltoid without any initial complication. The following day, the patient presented with an ecchymotic rash at the injection site, which was indurated and approximately 4 cm in diameter (Figure 1), and an erythematous malar rash (Figure 2), which she described as a raw sunburn. She also reported flu-like symptoms without fever: waves of hot pulsating heat, sweatiness, clamminess and fatigue. Two days after the galcanezumab injection, the patient’s facial rash became more erythematous, her systemic symptoms worsened, and she felt swelling around her lips and throat with purpuric discoloration in the lips. She was directed to the emergency room where she received intravenous methylprednisolone, diphenhydramine and famotidine. Laboratory investigations, including liver enzymes, basophils and eosinophils, were not elevated. Her airway symptoms improved, and she was discharged with a methylprednisolone dose pack. Six days after injection, the erythema began to fade and systemic symptoms began to improve. Another CGRP mAb has not been trialed.

Figure 1.

Left shoulder.

Figure 2.

Right cheek.

Discussion

This case presents a novel adverse reaction to Galcanezumab. Although a follow up meta-analysis in 2020 revealed additional adverse reactions: constipation (1.5%), vertigo (1.2%), generalized pruritus (1.2%) and injection site hypersensitivity (0.4%). No cases of systemic allergic reaction or anaphylaxis were noted (4). Only one case to date reports galcanezumab-induced anaphylaxis in a 47-year-old female with a history of asthma and a prior episode of topiramate-induced anaphylaxis (5). That patient experienced generalized pruritus, flushing, and throat and mouth swelling within 20 minutes of self-administering a subsequent dose of galcanezumab, most likely an immunoglobulin E (IgE)-mediated type I hypersensitivity reaction (5). Our case demonstrates a delayed type hypersensitivity reaction 1–2 days after an initial galcanezumab injection, with injection site reaction, facial rash and swelling, flu-like symptoms, and lip and throat swelling, resembling angioedema rather than a type I hypersensitivity reaction.

Three mechanisms have been implicated in immediate hypersensitivity reactions to mAb: cytokine release syndrome, IgE-mediated reactions and immunoglobulin G (IgG)-mediated reactions (6). Mixed reactions can occur with mAbs, and some reactions can develop hours after administration, especially when mAb is administered subcutaneously (6). Our patient experienced symptoms characteristic of cytokine release syndrome (flushing, throat tightness, fevers, chills), although this is more frequently seen in mAb that target cancer cells as a result of rapid destruction of cells and release of cytokines (6). The patient’s history of mast cell disorder and autoimmune disease adds further complexity. In a type I hypersensitivity IgE-mediated reaction, one would expect an immediate allergic reaction upon subsequent (not initial) exposure to mAb (6), as well as a faster progression of hypersensitivity response.

Although not clearly demonstrated in the literature, in type II or III hypersensitivity IgG-mediated reactions to mAb, the complement system could be activated by formation of large immune complexes (either exogenous mAb, endogenous antibodies or a combination of exogenous and endogenous antibodies), thereby generating anaphylatoxins (6). With a history of Hashimoto’s disease and laboratory findings suggestive of rheumatoid arthritis, this patient may have been more susceptible to forming antibody–antibody complexes upon exposure to galcanezumab, resulting in onset of her symptoms. Notably, the patient did not have worsening joint pain characteristic of IgG-mediated reactions, nor did she have any lower extremity rash or renal abnormality.

A delayed histamine-mediated reaction with angioedema properties could be potentially explained by the combination of the drug property and MCAS. Because of the size of the mAb, subcutaneous injection results in lymphatic, not vascular, uptake and spread, and the introduction of the mAb to circulating or antibodies or mast cells in distal tissue may take several days. Additionally, MCAS may have predisposed the mast cells to be more sensitive to histamine degranulation without the need for repeated exposure to the mAb. The possible absence of IgE involvement in this scenario would align with the lack of anaphylaxis and could be classified as a type IV rather than a type I hypersensitivity reaction, with mast cells rather than T-cells as the mediator.

Conclusions

Safety and efficacy of galcanezumab for chronic and episodic migraine have been demonstrated through the EVOLVE-2 trial and other subsequent meta-analyses; however, novel adverse reactions may continue to emerge. System allergic reaction to galcanezumab requiring emergency intervention may occur. It is unknown whether autoimmune or mast cell disorders may predispose patients to systemic reaction to galcanezumab or other mAb.

Clinical implications

A previously unreported systemic reaction to galcanezumab is described.

There was a reaction to monoclonal antibody in a patient with mildly positive antinuclear antibody.